MAP4K1(也称为HPK1)是一种丝氨酸/苏氨酸激酶,属于MAP4K家族,它位于人类染色体1q24.3上。MAP4K1在细胞信号传导中发挥重要作用,特别是在调节T细胞功能方面。该基因编码的蛋白质参与了多种生物学过程,包括细胞增殖、迁移、凋亡和炎症反应。
MAP4K1在多种癌症中表达上调,与肿瘤的发生和发展密切相关。研究发现,MAP4K1的表达水平与多种癌症患者的预后相关,包括淋巴瘤、肺癌、肝癌、宫颈癌和胃癌等。例如,在宫颈癌中,MAP4K1的表达上调与患者的生存率相关[2]。此外,MAP4K1还与T细胞功能失调有关,研究发现,在T细胞中敲除MAP4K1基因可以改善T细胞的功能,提高CAR-T细胞免疫疗法的疗效[1]。
MAP4K1的表达和活性受到多种因素的调控。例如,Pdcd4是一种肿瘤抑制因子,其表达下调可以导致MAP4K1的表达上调和AP-1依赖性转录的激活[3,5]。DLX6-AS1是一种长链非编码RNA,其表达上调可以促进胃癌细胞的增殖、迁移和EMT过程,而MAP4K1是DLX6-AS1的下游靶基因[4]。此外,CBX2和RUNX1也可以通过调控MAP4K1的表达影响结直肠癌的进展和化疗耐药性[6]。
MAP4K1的活性还受到磷酸酶的调控。DUSP家族的磷酸酶是MAP激酶信号通路的负调节因子,而MAP4K家族的激酶是MAP激酶信号通路的正调节因子。研究发现,在系统性红斑狼疮(SLE)患者的T细胞中,MAP4K1和DUSP22的表达下调,而MAP4K3和DUSP4的表达上调,表明MAP4K家族激酶和DUSP家族磷酸酶在T细胞信号传导和SLE发病机制中发挥重要作用[7]。
综上所述,MAP4K1是一种重要的丝氨酸/苏氨酸激酶,参与调节T细胞功能和多种癌症的发生和发展。MAP4K1的表达和活性受到多种因素的调控,包括Pdcd4、DLX6-AS1、CBX2和RUNX1等。MAP4K1的研究有助于深入理解T细胞信号传导和癌症发生机制,为癌症的治疗和预防提供新的思路和策略。
参考文献:
1. Si, Jingwen, Shi, Xiangjun, Sun, Shuhao, Wei, Lai, Liao, Xuebin. 2020. Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies. In Cancer cell, 38, 551-566.e11. doi:10.1016/j.ccell.2020.08.001. https://pubmed.ncbi.nlm.nih.gov/32860752/
2. Livesey, Michelle, Rossouw, Sophia Catherine, Blignaut, Renette, Christoffels, Alan, Bendou, Hocine. 2023. Transforming RNA-Seq gene expression to track cancer progression in the multi-stage early to advanced-stage cancer development. In PloS one, 18, e0284458. doi:10.1371/journal.pone.0284458. https://pubmed.ncbi.nlm.nih.gov/37093793/
3. Wang, Qing, Zhang, Yan, Yang, Hsin-Sheng. 2012. Pdcd4 knockdown up-regulates MAP4K1 expression and activation of AP-1 dependent transcription through c-Myc. In Biochimica et biophysica acta, 1823, 1807-14. doi:10.1016/j.bbamcr.2012.07.004. https://pubmed.ncbi.nlm.nih.gov/22801218/
4. Wu, Qiong, Ma, Jiali, Meng, Wenying, Hui, Pingping. 2019. DLX6-AS1 promotes cell proliferation, migration and EMT of gastric cancer through FUS-regulated MAP4K1. In Cancer biology & therapy, 21, 17-25. doi:10.1080/15384047.2019.1647050. https://pubmed.ncbi.nlm.nih.gov/31591939/
5. Yang, Hsin-Sheng, Matthews, Connie P, Clair, Timothy, Tan, Tse-Hua, Colburn, Nancy H. . Tumorigenesis suppressor Pdcd4 down-regulates mitogen-activated protein kinase kinase kinase kinase 1 expression to suppress colon carcinoma cell invasion. In Molecular and cellular biology, 26, 1297-306. doi:. https://pubmed.ncbi.nlm.nih.gov/16449643/
6. Wang, Bangting, Zhang, Shijie, Guo, Yumeng, Tang, Chunming, Liu, Li. 2025. CBX2 as a therapeutic target in colorectal cancer: insights into the altered chromatin accessibility via RUNX1-CBX2-MAP4K1 axis. In Oncogene, 44, 909-926. doi:10.1038/s41388-025-03331-1. https://pubmed.ncbi.nlm.nih.gov/40082555/
7. Chuang, Huai-Chia, Tan, Tse-Hua. 2019. MAP4K Family Kinases and DUSP Family Phosphatases in T-Cell Signaling and Systemic Lupus Erythematosus. In Cells, 8, . doi:10.3390/cells8111433. https://pubmed.ncbi.nlm.nih.gov/31766293/